Targeting Survivin with YM155 (Sepantronium Bromide): A novel therapeutic strategy for paediatric acute myeloid leukaemia

Smith, Amanda M.; Little, Erica; Zivanovic, Andjelija; Hong, Priscilla; Liu, Alfred K.S.; Burow, Rachel; Stinson, Caedyn L.; Hallahan, Andrew R.; Moore, Andrew S.

doi:10.1016/j.leukres.2015.01.005

Cited by 13 publications

(9 citation statements)

References 49 publications

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“…The leukemia cell lines used were Kasumi-1, derived from a childhood AML wild type for MLL but harboring a RUNX1-RUNX1T1 fusion (13), MV4-11, derived from a childhood myelomonocytic leukemia with a MLL-AFF1 fusion (14), ML-2, derived from an adult AML expressing MLL-MLLT4 (15) and THP-1, derived from a childhood AML expressing MLL-MLLT3 (16). Cell lines were sourced, validated, and cultured as described previously (17).…”

Section: Study Design and Sample Selectionmentioning

confidence: 99%

Targeted Next-Generation Sequencing for Detecting MLL Gene Fusions in Leukemia

Afrin

Zhang

Meyer

et al. 2018

Molecular Cancer Research

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Mixed lineage leukemia () gene rearrangements characterize approximately 70% of infant and 10% of adult and therapy-related leukemia. Conventional clinical diagnostics, including cytogenetics and fluorescence hybridization (FISH) fail to detect translocation partner genes (TPG) in many patients. Long-distance inverse (LDI)-PCR, the "gold standard" technique that is used to characterize breakpoints, is laborious and requires a large input of genomic DNA (gDNA). To overcome the limitations of current techniques, a targeted next-generation sequencing (NGS) approach that requires low RNA input was tested. Anchored multiplex PCR-based enrichment (AMP-E) was used to rapidly identify a broad range of fusions in patient specimens. Libraries generated using Archer FusionPlex Heme and Myeloid panels were sequenced using the Illumina platform. Diagnostic specimens ( = 39) from pediatric leukemia patients were tested with AMP-E and validated by LDI-PCR. In concordance with LDI-PCR, the AMP-E method successfully identified TPGs without prior knowledge. AMP-E identified 10 different fusions in the 39 samples. Only two specimens were discordant; AMP-E successfully identified a fusion where LDI-PCR had failed to determine the breakpoint, whereas a fusion was not detected by AMP-E due to low expression of the fusion transcript. Sensitivity assays demonstrated that AMP-E can detect in MV4-11 cell dilutions of 10 and transcripts down to 0.005 copies/ng. This study demonstrates a NGS methodology with improved sensitivity compared with current diagnostic methods for -rearranged leukemia. Furthermore, this assay rapidly and reliably identifies partner genes and patient-specific fusion sequences that could be used for monitoring minimal residual disease. .

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Section: Study Design and Sample Selectionmentioning

confidence: 99%

Targeted Next-Generation Sequencing for Detecting MLL Gene Fusions in Leukemia

Afrin

Zhang

Meyer

et al. 2018

Molecular Cancer Research

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“…Antibodies used for immunoblotting included anti-pMEK1/2(Ser217/221), -MEK1/2 total, -ERK1/2(Thr202/Tyr204), -ERK1/2 total, PARP, -pAKT (S473), -AKT, pCREB (S133) and CREB (Cell Signalling Technology, Inc., MA, USA) and anti-GAPDH (Millipore, USA). Membranes were incubated with IRDye ® 680LT or IRDye 800CW conjugated secondary antibodies and protein-antibody complexes visualized as previously described [48].…”

Section: Methodsmentioning

confidence: 99%

PTEN deletion drives acute myeloid leukemia resistance to MEK inhibitors

et al. 2019

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Kinases such as MEK are attractive targets for novel therapy in cancer, including acute myeloid leukaemia (AML). Acquired and inherent resistance to kinase inhibitors, however, is becoming an increasingly important challenge for the clinical success of such therapeutics, and often arises from mutations in the drug-binding domain of the target kinase. To identify possible causes of resistance to MEK inhibition, we generated a model of resistance by long-term treatment of AML cells with AZD6244 (selumetinib). Remarkably, resistance to MEK inhibition was due to acquired PTEN haploinsufficiency, rather than mutation of MEK. Resistance via this mechanism was confirmed using CRISPR/Cas9 technology targeting exon 5 of PTEN. While PTEN loss has been previously implicated in resistance to a number of other therapeutic agents, this is the first time that it has been shown directly and in AML.

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“…ATRA and ATO lead to complete remission in most patients with APL, but a large proportion of patients eventually experience relapse 2 , 26 . Therefore, novel therapeutic targets are necessary to improve the outcomes for patients with APL 27 . YAP functions as an oncoprotein by interacting with TEAD, forming a protein complex critical for the transcription of downstream genes such as c-Myc and Survivin 15 , 22 .…”

Section: Discussionmentioning

confidence: 99%

“…Using a CCK-8 assay, we showed that cell proliferation was significantly inhibited in both YAP knockdown and VP treatment groups, compared with control group. Inhibition of Survivin expression could promote apoptosis in leukemia cells 27 , 30 . Here, we observed that the expression levels of Survivin and cyclinD1decreased in YAP knockdown and VP treatment groups, compared with control groups.…”

Section: Discussionmentioning

confidence: 99%

Effect of YAP Inhibition on Human Leukemia HL-60 Cells

et al. 2017

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Background: Yes-associated protein (YAP), the nuclear effector of the Hippo pathway, is a candidate oncoprotein and participates in the progression of various malignancies. However, few reports have examined the effect of YAP inhibition in human leukemia HL-60 cells.Methods: We examined the effects of YAP knockdown or inhibition using short hairpin RNA (shRNA) or verteporfin (VP), respectively. Western blot assays were used to determine the expression levels of YAP, Survivin, cyclinD1, PARP, Bcl-2, and Bax. Cell proliferation was assessed using the cell counting kit (CCK-8) assay. Cell cycle progression and apoptosis were evaluated by flow cytometry, and apoptotic cell morphology was observed by Hoechst 33342 staining.Results: Knockdown or inhibition of YAP led to cell cycle arrest at the G0/G1 phase and increased apoptosis, inhibited cell proliferation, increased levels of Bax and cleaved PARP, and decreased levels of PARP, Bcl-2, Survivin, and cyclinD1. Moreover, Hoechst 33342 staining revealed increased cell nuclear fragmentation.Conclusion: Collectively, these results show that inhibition of YAP inhibits proliferation and induces apoptosis in HL-60 cells. Therefore, a novel treatment regime involving genetic or pharmacological inhibition of YAP could be established for acute promyelocytic leukemia.

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Targeting Survivin with YM155 (Sepantronium Bromide): A novel therapeutic strategy for paediatric acute myeloid leukaemia

Cited by 13 publications

References 49 publications

Targeted Next-Generation Sequencing for Detecting MLL Gene Fusions in Leukemia

Targeted Next-Generation Sequencing for Detecting MLL Gene Fusions in Leukemia

PTEN deletion drives acute myeloid leukemia resistance to MEK inhibitors

Effect of YAP Inhibition on Human Leukemia HL-60 Cells

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